Native Amino Group Directed Site-Selective ε-C(sp²)–H Iodination of Primary Amines

Abstract

Selective remote C–H activating amines using unmodified NH2 as a native directing group demonstrate compelling synthetic utilities. The 3-arylpropan-1-amine moiety is present in many drugs and candidates in clinical trials. Selective iodination of 3-arylpropan-1-amines on remote aryl rings gives valuable intermediates for modifying bioactive molecules and synthesizing quinolones. Here we report the first palladium-catalyzed selective ε-C(sp2)–H iodination of free 3-arylpropan-1-amines via a seven-membered palladacycle.

Native Amino Group Directed Meta-Selective C–H Arylation of Primary Amines Via Pd/Norbornene Catalysis

“…In a previous report, we detailed the ε-C(sp 2 )−H iodination of 3-arylpropan-1-amine facilitated by the native amino group assistant. 11 Prompted by this, we sought to investigate whether the transient mediator could facilitate activation of the metaposition. To explore this, deuterium/hydrogen scrambling experiments were conducted, utilizing unprotected primary amines 1g and 1a′ as the substrates (Scheme 2).…”

“…In a previous report, we detailed the ε-C­(sp 2 )–H iodination of 3-arylpropan-1-amine facilitated by the native amino group assistant . Prompted by this, we sought to investigate whether the transient mediator could facilitate activation of the meta -position.…”

Ligand-Enabled Palladium(II)-Catalyzed γ-C(sp3)–H Arylation of Primary Aliphatic Amines

“…To further overcome the substrate limitation, Li introduced pyridone as a ligand and achieved normal primary amine-directed γ-C­(sp 3 )–H arylation . Despite these achievements, to date, an alternative and efficient catalytic system for challenging normal primary amine-directed C­(sp 3 )–H functionalization remains highly coveted …”